Nonsteroidal Anti-inflammatory
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
Sulindac, a prostaglandin synthesis inhibitor, potentially could cause constriction of the ductus arteriosus in utero, as well as inhibition of labor, prolongation of pregnancy, and suppression of fetal renal function (1,2). Persistent pulmonary hypertension of the newborn should also be considered (3). Women attempting to conceive should not use any prostaglandin synthesis inhibitor, including sulindac, because of the findings in a variety of animal models that indicate these agents block blastocyst implantation (4,5). Moreover, as noted below, nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with spontaneous abortions (SABs) and congenital malformations. The absolute risk for these defects, however, appears to be low.
FETAL RISK SUMMARY
Sulindac is an NSAID prodrug that is converted in vivo to the biologically active sulfide metabolite. It is used for the relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis, gouty arthritis, ankylosing spondylitis, and acute painful shoulder (6). Sulindac is in the same NSAID subclass (acetic acids) as diclofenac, indomethacin, and tolmetin. However, sulindac, a derivative of indomethacin, is seven times more cyclooxygenase (COX)-2 selective than indomethacin and is sometimes referred to as a COX-2 selective agent (7).
When administered to pregnant rats, similar to other NSAIDs, sulindac reduces fetal weight and pup survival (at doses ≥2.5 times than the usual maximum human daily dose), prolongs the duration of gestation, and may cause dystocia (6,8).
Consistent with the molecular weight (about 356), sulindac and its active metabolite cross the human placenta to the fetus. Nine women at a mean gestational age of 31.8 weeks (24.3–36.4 weeks) were given a single 200-mg oral dose of the drug a mean 5.5 hours (4.4–6.7 hours) before cordocentesis (9,10). Maternal serum was obtained at a mean 5.8 hours (3.5–7.3 hours) after the dose. The mean concentrations of sulindac in the mothers and fetuses were 0.59 and 0.98 mcg/mL, respectively, and of the sulfide metabolite 1.42 and 0.68 mcg/mL, respectively. The corresponding sulfide:sulindac ratios in the mother and fetal compartments were 2.32 and 0.53, respectively. The reduced amounts of metabolite in the fetus, compared with those in the mother, were thought to be caused by decreased placental transfer of the metabolite and slower metabolism of sulindac in the fetus (10). Because of these findings, the investigators theorized that, as a tocolytic, sulindac would be expected to cause less fetal toxicity than indomethacin.
Using a human term placental perfusion model, a 1999 study demonstrated that the sulfide metabolite reaches the fetus in higher concentrations than does sulindac or indomethacin (11). The fetal:maternal ratios after 2-hour perfusions were 0.34 (sulindac), 0.54 (sulfide metabolite), and 0.45 (indomethacin). Neither sulindac nor indomethacin was metabolized by the placenta (11).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 69 newborns had been exposed to sulindac during the 1st trimester (F. Rosa, personal communication, FDA, 1995). Three (4.3%) major birth defects were observed (three expected), including one cardiovascular defect (one expected). No anomalies were observed in five other categories of defects (oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available. For exposure during any trimester (102 newborns), two malformations of the eyeball (excluding oculomotor and ptosis) were observed (none expected), but no brain defects were recorded.
A combined 2001 population-based, observational cohort study and a case–control study estimated the risk of adverse pregnancy outcome from the use of NSAIDs (12). The use of NSAIDs during pregnancy was not associated with congenital malformations, preterm delivery, or low birth weight, but a positive association was discovered with SABs. A similar study, also published in 2001, failed to find a relationship, in general, between NSAIDs and congenital malformations, but did find a significant association with cardiac defects and orofacial clefts (13). In addition, a 2003 study found a significant association between exposure to NSAIDs in early pregnancy and SABs (14). (See Ibuprofen for details on these three studies.)
A brief 2003 editorial on the potential for NSAID-induced developmental toxicity concluded that NSAIDs, specifically those with greater COX-2 affinity, had a lower risk of this toxicity in humans than aspirin (15).
An abstract and a full report, both published in 1992, described the use of sulindac in the treatment of preterm labor in comparison with indomethacin (16,17). The gestational ages at treatment for the groups were 29 and 30 weeks, respectively. The sulindac group (N = 18) received 200 mg orally every 12 hours for 48 hours, whereas those receiving indomethacin (N = 18) were given 100 mg orally once followed by 25 mg orally every 4 hours for 48 hours. Both groups received IV magnesium sulfate and some in both groups received SC terbutaline. The response to tocolysis was statistically similar for sulindac and indomethacin. However, the sulindac-treated women had significantly greater hourly fetal urine output, the deepest amniotic fluid pocket, and the largest amniotic fluid index. Patent ductus arteriosus (PDA) was observed in 11% vs. 22%, respectively, and intraventricular hemorrhage (IVH) in the newborn occurred in 11% of both groups. These differences were not significant. No cases of primary pulmonary hypertension in the newborns were observed (16,17).
A comparison between sulindac (200 mg orally every 12 hours for 4 days) and indomethacin (100 mg rectally on the 1st day, then 50 mg orally every 8 hours for 3 days) on fetal cardiac function was published in 1995 (18). Each group was composed of 10 patients with threatened premature labor at 28–32 weeks’ gestation. Significant reductions in the mean pulsatility index of the fetal ductus arteriosus began 4 hours after the first indomethacin dose. The reduction increased with time and resolved 24 hours after the last dose. Other secondary changes in fetal cardiac function resulting from ductal constriction were also noted. In the sulindac group, a significant decrease in the mean pulsatility index, without secondary changes, was observed only at 24 hours (18).
A study comparing the fetal cardiovascular effects of sulindac (200 mg orally every 12 hours) and terbutaline (5 mg orally every 4 hours) for 68 hours at an approximate mean gestational age of 32 weeks was published in an abstract form in 1996 (19) and in a full report in 1999 (20). Significant ductal constriction was noted only in the sulindac group. In contrast to the study cited above, therapy was stopped because of severe constriction in 2 (one at 12 hours and the other at 24 hours) of the 10 patients. The constriction of the fetal ductus arteriosus occurred within 5 hours of receiving sulindac and resolved within 48 hours of discontinuing the drug (19,20).
A 1994 abstract reported that the tocolytic effect of a 7-day course of sulindac, 200 mg orally every 12 hours, following arrest of labor with IV magnesium sulfate, was no different from placebo and observation (21). The difference in prolongation of pregnancy between the sulindac (N = 13) and placebo (N = 15) groups (33 vs. 26 days, respectively) was not significant. No differences between the groups on days 0, 7, and 14 were found for hourly fetal urine production, amniotic fluid index, or ductus arteriosus velocity (21).
Two 1995 references from the same group of investigators, using a similar study design, concluded that sulindac did not reduce the rate of premature birth but did lengthen the interval to retocolysis in those patients who required retocolysis (22,23). No difference was found between sulindac and placebo in prolongation of pregnancy, delivery at >35 weeks’ gestation, recurrent preterm labor, birth weight, or time spent in the neonatal intensive care unit. No adverse effects were observed in the exposed fetuses (22,23).
As demonstrated with other NSAIDs (see also Indomethacin), sulindac reduces amniotic fluid volume by decreasing fetal urine output in a dose-related manner (24). Sulindac, 200 mg twice daily, was given to the mothers of three sets of monoamniotic twins, diagnosed as having cord entanglement, beginning at 24, 27, and 29 weeks, respectively, and continued until elective cesarean section at 32 weeks’ gestation. One of the twins had a preexisting heart defect (transposition of the great vessels and a ventricular septal defect). The dose was reduced in one patient to 200 mg/day to maintain an adequate amniotic fluid index. No significant changes in the umbilical artery or the ductus arteriosus Doppler waveforms were observed. All of the newborns had appropriate weights for gestation and normal renal function during the first week of life, and none required ventilation (24).
A 2000 abstract described a retrospective case–cohort study that compared the neonatal effects of sulindac with indomethacin (25). The infants (born between 1994 and 1999) had been exposed to antenatal sulindac (N = 25) or indomethacin (N = 66) and weighed <1500 g. Those exposed to both drugs or with congenital abnormalities were excluded. There were no significant differences between the indomethacin and sulindac groups in IVH (32% vs. 36%), grades III-IV IVH (14% vs. 12%), necrotizing enterocolitis (8% vs. 8%), serum creatinine >1.4 mg/dL (19% vs. 15%), PDA (17% vs. 28%), and mortality (12% vs. 12%), respectively. However, there was a significant increase in the risk for bronchopulmonary dysplasia after exposure to indomethacin (adjusted odds ratio 4.9, 95% confidence interval 1.01–23.44) (25).
A 2003 review concluded that COX-2 selective drugs, such as sulindac, should only be used as tocolytics in randomized controlled trials (7). This conclusion was based on the uncertainty over whether the fetal toxicity observed with sulindac resulted from COX-2-dependent effects, or from fetal accumulation of drug levels sufficient to cause COX-1 inhibition (7).
BREASTFEEDING SUMMARY
No reports describing the use of sulindac during lactation have been located. The mean adult serum half-life of the biologically active sulfide metabolite is 16.4 hours (6). One reviewer concluded that because of the prolonged half-life, other agents in this class (diclofenac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, ketorolac, and tolmetin) were safer alternatives if an NSAID was required during nursing (26).
References
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2.Fuchs F. Prevention of prematurity. Am J Obstet Gynecol 1976;126:809–20.
3.Van Marter LJ, Leviton A, Allred EN, Pagano M, Sullivan KF, Cohen A, Epstein MF. Persistent pulmonary hypertension of the newborn and smoking and aspirin and nonsteroidal antiinflammatory drug consumption during pregnancy. Pediatrics 1996;97:658–63.
4.Matt DW, Borzelleca JF. Toxic effects on the female reproductive system during pregnancy, parturition, and lactation. In: Witorsch RJ, ed. Reproductive Toxicology. 2nd ed. New York, NY: Raven Press, 1995: 175–93.
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11.Lampela ES, Nuutinen LH, Ala-Kkokko TL, Parikka RM, Laitinen RS, Jouppila PI, Vahakangas KH. Placental transfer of sulindac, sulindac sulfide, and indomethacin in a human placental perfusion model. Am J Obstet Gynecol 1999;180:174–80.
12.Nielsen GL, Sorensen HT, Larsen H, Pedersen L. Risk of adverse birth outcome and miscarriage in pregnant users of non-steroidal anti-inflammatory drugs: population-based observational study and case–control study. Br Med J 2001;322:266–70.
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16.Carlan SJ, O’Brien WF, O’Leary TD, Mastrogiannis DS. A randomized comparative trial of indomethacin and sulindac for the treatment of refractory preterm labor (abstract). Am J Obstet Gynecol 1992; 166:361.
17.Carlan SJ, O’Brien WF, O’Leary TD, Mastrogiannis D. Randomized comparative trial of indomethacin and sulindac for the treatment of refractory preterm labor. Obstet Gynecol 1992;79:223–8.
18.Rasanen J, Jouppila P. Fetal cardiac function and ductus arteriosus during indomethacin and sulindac therapy for threatened preterm labor: a randomized study. Am J Obstet Gynecol 1995;173:20–5.
19.Kramer W, Saade G, Belfort M, Dorman K, Mayes M, Moise K Jr. Randomized double-blind study comparing sulindac to terbutaline: fetal cardiovascular effects (abstract). Am J Obstet Gynecol 1996; 174:326.
20.Kramer WB, Saade GR, Belfort M, Dorman K, Mayes M, Moise KJ Jr. A randomized double-blind study comparing the fetal effects of sulindac to terbutaline during the management of preterm labor. Am J Obstet Gynecol 1999;180:396–401.
21.Carlan S, Jones M, Schorr S, McNeill T, Rawji H, Clark K. Oral sulindac to prevent recurrence of preterm labor (abstract). Am J Obstet Gynecol 1994;170:381.
22.Jones M, Carlan S, Schorr S, McNeill T, Rawji R, Clark K, Fuentes A. Oral sulindac to prevent recurrence of preterm labor (abstract). Am J Obstet Gynecol 1995;172:416.
23.Carlan SJ, O’Brien WF, Jones MH, O’Leary TD, Roth L. Outpatient oral sulindac to prevent recurrence of preterm labor. Obstet Gynecol 1995;85:769–74.
24.Peek MJ, McCarthy A, Kyle P, Sepulveda W, Fisk NM. Medical amnioreduction with sulindac to reduce cord complications in monoamniotic twins. Am J Obstet Gynecol 1997;176:334–6.
25.Sciscione A, Leef K, Vakili B, Paul D. Neonatal effects after antenatal treatment with indomethacin vs. sulindac (abstract). Am J Obstet Gynecol 2000;182:S66.
26.Anderson PO. Medication use while breast feeding a neonate. Neonatal Pharmacol Q 1993;2:3–14.